The goal of these proposed studies is to investigate the molecular basis of neurosecretion in adrenal chromaffin cells, with particular emphasis on the role played by voltage-sensitive Na+ channels. The specific aims of this proposal include determination of the molecular structure of adrenal chromaffin cell Na+ channels by molecular cloning techniques, expression of those Na+ channels in Xenopus oocytes and mammalian cells to assess their physiological and pharmacological properties, and finally, ablation of selected Na+ channel genes in adrenal chromaffin cells in primary culture using antisense mRNA technology to determine which aspects of catecholamine neurosecretion are contributed by specific Na+ channel subunits. I hypothesize that because Na+ channels in other tissues are functionally modulated by auxiliary beta subunits, Na+ channel beta subunits in adrenal chromaffin cells will modulate neuroendocrine Na+ channels and therefore make a significant contribution to the regulation of neurosecretion.